Highly regioselective radical cyclizations of allenamides

Article abstract of DOI:10.1021/ol047572z

(Chemical Equation Presented) The first radical cyclizations of allenamides are described. These reactions are highly regioselective for the central carbon of the allenic moiety, leading to an efficient preparation of nitrogen heterocycles such as isoquin

Full text of DOI:10.1021/ol047572z

ORGANIC
LETTERS
2005
Vol. 7, No. 5
775-778
Highly Regioselective Radical
Cyclizations of Allenamides
Lichun Shen and Richard P. Hsung*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received November 25, 2004
ABSTRACT
The first radical cyclizations of allenamides are described. These reactions are highly regioselective for the central carbon of the allenic
moiety, leading to an efficient preparation of nitrogen heterocycles such as isoquinolines, and carbocycles such as indane and naphthalene
derivatives. The exo-cyclization mode could also be achieved in some cases, leading to the synthesis of isoindoles. The feasibility of a
tandem radical cyclization using allenamide is also established.
Radical reactions represent a powerful tool in organic
synthesis.1-4 Our efforts in developing synthetic methods
employing allenamides5-7 led us to speculate on the pos-
sibility of a radical cyclization using allenamides 1 [Figure
1]. In addition to achieving a new approach for constructing
nitrogen heterocycles [see 4, 6, or 8], this investigation
presents a unique opportunity to address the regioselectivity
issue in radical processes involving allenes: endo- versus
central- versus exo-cyclization, which is not a well-resolved
problem.8-11
respectively, central-cyclization would give the energetically
more favored allyl radical 5 [Figure 1]. Since this is an
intramolecular radical process, endo-cyclization may be
prohibited due to geometric constraints. With these issues
in mind, we investigated radical cyclizations of allenamides.
We report here a highly regioselective radical cyclization of
allenamides for syntheses of isoquinolines and isoindoles.
While both endo- and exo-cyclizations of radical inter-
mediate 2 would lead to new vinyl radicals 3 and 7,
(1) For recent reviews, see: (a) Sibi, M. P.; Manyem, S.; Zimmerman,
J. Chem. ReV. 2003, 103, 3263. (b) Rheault, T. R.; Sibi, M. Synthesis 2003,
803. (c) Gansa¨uer, A.; Bluhm, H. Chem. ReV. 2000, 100, 2771. (d)
Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99,
1991.
(2) (a) Sibi, M. P.; He, L. Org. Lett. 2004, 6, 1749. (b) Cook, G. R.;
Sun, L. Org. Lett. 2004, 6, 2481. (c) Cook, G. R.; Maity, B. C.; Kargbo, R.
Org. Lett. 2004, 6, 1741. (d) Crich, D.; Shiral, M.; Rumthao, S. Org. Lett.
2003, 5, 3767. (e) Marion, F.; Courillon, C.; Malacria, M. Org. Lett. 2003,
5, 5095.
(3) (a) Liu, L.; Wang, X.; Li, C. Org. Lett. 2003, 5, 361. (c) Yu, H.; Li,
C. J. Org. Chem. 2004, 69, 142.
(4) For recent examples of tandem radical cyclizations, see: (a) Lee,
H.-Y.; Lee, S.; Kim, B. G.; Bahn, J. S. Tetrahedron Lett. 2004, 45, 7225.
(b) Allan, G. M.; Parsons, A. F.; Pons, J.-F. Synlett 2002, 1431.
(5) For a review, see: Hsung, R. P.; Wei, L.-L.; Xiong, H. Acc. Chem.
Res. 2003, 36, 773.
Figure 1.
10.1021/ol047572z CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/10/2005

Table 1.
entry
SM
initiator [equiv]
H-donor [equiv]
temp (°C)
solventa
product
yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
12a
12a
12a
12a
12a
12b
12b
12b
12b
12b
12b
12b
12b
12b
AIBN [0.4]
AIBN [0.4]
Et3B/air
n-Bu3SnH [2.0]
n-Bu3SnH [2.0]
TMS3SiH [1.1]
TMS3SiH [2.0]
TMS3SiH [1.1]
n-Bu3SnH [1.5]
n-Bu3SnH [1.5]
TMS3SiH [1.1]
PhSH
80
110
50
50
50
80
80
80
80
80
rt
PhH
tol
tol
tol
tol
tol
told
tol
tol
tol
no rxnc
no rxnc
decomp
decomp
decomp
66%
44
10
no rxne
no rxne
10
Et3B/air
[PhCO]2O2 [0.2]
AIBN [0.4]
AIBN[0.4]
AIBN[0.4]
AIBN[0.4]
AIBN[0.4]
Et3B/air
Et3B/air
[PhCO]2O2[0.2]
[PhCO]2O2[0.2]
14
14
14
t-BuSH
n-Bu3SnH [2.0]
TMS3SiH [1.1]
n-Bu3SnH [2.0]
n-Bu3SnH [2.0]
tol
tol
tol
told
14
14
14
14
rt
60
60
8
44
48
a Concentration is 0.05 M unless otherwise noted. b Isolated yield. c Partial recovery of 12a and decompositions. d Concentration ) 0.01 M. e Addition of
thiols to allene were found in high yields.
To establish the feasibility, allenamides 12a and 12b12 with
either a bromo- or iodo-benzyl group substituted at the
nitrogen atom [N-tethered] were prepared from aryl halides
9a and 9b, respectively, in good overall yields [Scheme 1].
This preparation features base-induced isomerization,13 which
still represents the most reliable and facile synthetic entry
to various allenamides.
(6) For recent allenamide chemistry, see: (a) An˜orbe, L.; Poblador, A.;
Dom´ınguez, G.; Pe´rez-Castells, J. Tetrahedron Lett. 2004, 45, 4441. (b)
Achmatowicz, M.; Hegedus, L. S. J. Org. Chem. 2004, 69, 2229. (c)
Ranslow, P. D. B.; Hegedus, L. S.; de los Rios, C. J. Org. Chem. 2004, 69,
105. (d) Bacci, J. P.; Greenman, K. L.; Van Vranken, D. L. J. Org. Chem.
2003, 68, 4955. (e) Armstrong, A.; Cooke, R. S.; Shanahan, S. E. Org.
Biomol. Chem. 2003, 1, 3142. (f) Gaul C.; Seebach, D. HelV. Chim. Acta
2002, 85, 963. (g) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002, 43, 1499.
(h) Nair, V.; Sethumadhavan, D.; Nair, S. M.; Shanmugam, P.; Treesa, P.
M.; Eigendorf, G. K. Synthesis 2002, 1655. (i) Kozawa, Y.; Mori, M.
Tetrahedron Lett. 2001, 42, 4869. (j) Kinderman, S. S.; van Maarseveen,
J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. T., Org. Lett. 2001,
3, 2045. (k) van Boxtel, L. J.; Korbe, S.; Noltemeyer, M.; de Meijere, A.
Eur. J. Org. Chem. 2001, 2283. (l) Grigg, R.; Ko¨ppen, I.; Rasparini, M.;
Sridharan, V. Chem. Commun. 2001, 964. (m) For papers before 2001, see
ref 5.
Scheme 1
(7) For our recent efforts, see: (a) Huang, J.; Hsung. R. P. J. Am. Chem.
Soc. 2005, 127, 50. (b) Rameshkumar, C.; Hsung, R. P. Angew Chem., Int.
Ed. 2004, 43, 615. (c) Berry, C. R.; Hsung, R. P. Tetrahedron 2004, 60,
7629. (d) Xiong, H.; Huang, J.; Ghosh, S.; Hsung, R. P. J. Am. Chem. Soc.
2003, 125, 12694. (e) Rameshkumar, C.; Hsung, R. P. Synlett 2003, 1241.
(f) Berry, C. R.; Rameshkumar, C.; Tracey, M. R.; Wei, L.-L.; Hsung, R.
P. Synlett 2003, 791. (g) Rameshkumar, C.; Xiong, H.; Tracey, M. R.; Berry,
C. R.; Yao, L. J.; Hsung, R. P. J. Org. Chem. 2002, 67, 1339. (h) Xiong,
H.; Hsung. R. P.; Berry, C. R.; Rameshkumar, C. J. Am. Chem. Soc. 2001,
123, 7174.
(8) For leading references on Bergman cyclizations involving allenes,
see: (a) Grissom, J. W.; Klingberg, D.; Huang, D.; Slattery, B. J. J. Org.
Chem. 1997, 62, 603. (b) Grissom, J. W.; Huang, D. Angew. Chem., Int.
Ed. Engl. 1995, 34, 2037. (c) Grissom, J. W.; Klingberg, D. Tetrahedron
Lett. 1995, 36, 6607. (d) Grissom, J. W.; Huang, D. J. Org. Chem. 1994,
59, 5114.
(9) Also see: (a) Myers, A. G.; Dragovich, P. S. J. Am. Chem. Soc.
1989, 111, 9130. (b) Myers, A. G.; Kuo, E. Y.; Finney, N. S. J. Am. Chem.
Soc. 1989, 111, 8057.
(10) Wang, K. K.; Zhang, H.-R.; Petersen, J. L. J. Org. Chem. 1999,
64, 1650.
(11) For other related references, see: (a) Schmittel, M.; Strittmatter,
M.; Kiau, S. Tetrahedron Lett. 1995, 36, 4975. (b) Krause, N.; Hohmann,
M. Synlett 1996, 89. (c) Gillmann, T.; Hu¨lsen, T.; Massa, W.; Wocadlo, S.
Synlett 1995, 1257.
Given the lack of precedent in radical cyclizations using
allenamides, N-tethered allenamides 12a and 12b were
employed in the screening of a range of conditions. As
summarized in Table 1, it appears that only iodide is a
suitable radical precursor as only the iodo-benzyl substituted
allenamide 12b underwent cyclizations [entries 6-14],
(12) All new compounds were characterized by 1H NMR, 13C NMR,
FTIR, [R]20D, and MS; see Supporting Information.
776
Org. Lett., Vol. 7, No. 5, 2005

whereas 12a was not useful [entries 1-5]. In addition,
although AIBN is a better initiator than benzoyl peroxide
[entries 6 and 7 versus 13 and 14], n-Bu3SnH appears to be
the best hydrogen donor, with optimal reaction temperature
being 80 °C and concentration at 0.05 M [entry 6 versus
7].14 Most significantly, only isoquinoline 14 was isolated
as a consequence of a highly regioselective radical cyclization
onto the central carbon b. Neither the endo-cyclized product
isobenzazepin 13 nor the exo-cyclized product isoindole 15
was found.
Scheme 3
This specific regioselectivity is further displayed using a
range of different allenamides 16a-f that contains a urethane
[entries 1 and 2], urea [entry 3], or amido substitution [entries
4-6] [Table 2]. These results suggest that the electronic
radical cyclization of 20 led to indene 22 in 70% yield as
the exclusive product. Allenamide 21 with an extra methylene
unit [see the box] was also suitable for the radical cyclization
and afforded only the central-cyclized product dihydronaph-
thalene 23. The exo-cyclized Indane product 24 was not
found.
Table 2.
It was surprising, then, to find that reactions of N-tethered
allenamides 25 and 26, containing a carbonyl group [see the
box] at the tethering, did give exo-cyclized products [Scheme
4]. In fact, the exo-cyclization product 27 was the major
entry
allenamides
16a: R ) OtBu
16b: R ) O-(+)-menthyl
16c: R ) NMe2
16d: R ) Me
16e: R ) [CH2]2CHdCH2
16f: R ) isopropenyl
product
yielda (%)
1
2
3
4
5
6
17a
17b
17c
17d
17e
17f
75
80
69
58
55b
44c
Scheme 4
a Isolated yield. b 42% and 46% yields at 0.01 and 0.005 M, respectively.
c 44% yield at 0.01 M.
nature of the allenamide nitrogen atom has no impact on
the regioselectivity. In addition, cyclization of allenamide
18 substituted with an iodo-phenyl group [one less methylene
unit than 12b] was also feasible in favor of central-
cyclization, providing indole 19 in 91% yield [Scheme 2].
Scheme 2
product. Although the overall yield is a modest 35%, this
establishes the possibility of allenamide radical cyclization
in an exo-mode.
The use of allenamide 26 containing a chiral auxiliary
further demonstrates the feasibility of an exo-cyclization and
(14) Typical Experimental Procedure. A solution of allenamide 16a
(175.5 mg, 0.47 mmol) and AIBN (0.4 equiv, 30.8 mg) in toluene (9.4
mL) was heated to 80 °C for 5 min, after which, n-Bu3SnH (1.5 equiv,
189.5 µL) was added dropwise via a syringe. [Note: a syringe pump was
used for the tandem reaction.] The reaction was heated at 80 °C for 3 h
before being cooled to room temperature. A saturated aqueous KF solution
(5 mL) was then added, and the mixture was stirred for another 2 h at
room temperature. After filtration through Celite, the biphasic filtrate was
extracted with 5 mL of EtOAc. The aqueous layer was extracted with another
5 mL portion of EtOAc after separation. The combined organic extracts
were concentrated under reduced pressure, and the crude residue was purified
using flash silica gel column chromatography (gradient eluent: 0-10%
EtOAc in hexane) to provide 86.1 mg (75% yield) of compound 17a as
thick yellow oil.
We next examined allenamides 20 and 21 with the aryl
iodide group tethered through the R-carbon of the allenamide
[C-tethered] Scheme 3]. Their preparations involved the
R-lithiation and alkylation of the corresponding unsubstituted
allenamide.15 Employing similar reaction conditions, the
(13) (a) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron
Lett. 1999, 40, 6903. (b) Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.; Douglas,
C. J.; Xiong, H.; Mulder, J. A. Org. Lett. 1999, 1, 1237. (c) Wei, L.-L.;
Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C. J.; Hsung, R. P.
Tetrahedron 2001, 57, 459. (d) Huang, J.; Xiong, H.; Hsung, R. P.;
Rameshkumar, C.; Mulder, J. A.; Grebe, T. P. Org. Lett. 2002, 4, 2417.
(15) Xiong, H.; Hsung, R. P.; Wei, L.-L.; Berry, C. R.; Mulder, J. A.;
Stockwell, B. Org. Lett. 2000, 2, 2869.
Org. Lett., Vol. 7, No. 5, 2005
777

provided the exo-product 29 as a single diastereomer,16
although the exo to central ratio dropped to 1.6:1. The sp2
hybridized carbonyl carbon evidently provides sufficient
constraint to allow a better exo-cyclization trajectory onto
carbon c.
be derived from an initial exo-cyclization of allenamide 31,
likely through the rotamer 31a via radical intermediates 34a
and 35.
We also isolated the bridged heterocycle 36 in 17% yield
[Scheme 5]. This is most likely a result of an initial radical
cyclization onto not the allenic motif but the allyl group in
rotamer 31b given the favorable proximity, leading to a
secondary radical intermediate 37 prior to cyclization onto
the allene. We are currently exploring optimization of this
radical cyclization pathway.18
We were able to subsequently pursue a tandem radical
cyclization4,8 using allenamide 31 as shown in Scheme 5.
Scheme 5
Finally, it is noteworthy that an initial exo-cyclization onto
the allenic motif [see 35] appears to be prerequisite for
completing the tandem process. In the case of allenamide
16e [Scheme 5], although a tandem cyclization could have
occurred under the same reaction conditions, leading to 40
after an initial central-cyclization, it was not observed.
Instead, the allyl radical intermediate 39 was simply trapped
to give the corresponding isoquinoline 17e [see Table 2].
This difference can be attributed to the fact that the more
stable allyl radical 39 was simply not as reactive, and thus
the second cyclization was much slower relative to abstrac-
tion of hydrogen from n-Bu3SnH.
We have described here the first radical cyclizations
employing allenamides. These reactions are highly regio-
selective for the central carbon in the allenic motif, leading
to a useful preparation of isoquinolines as well as derivatives
of indole, indane, and naphthalene. The exo-cyclization mode
could be achieved in some cases and led to the formation of
isoindoles. The feasibility of a tandem radical cyclization
was also established. Applications employing this new radical
cyclization are underway.
Acknowledgment. The authors thank NSF [CHE-
0094005] for support.
Syringe pump addition of n-Bu3SnH was needed for this
reaction, and under these conditions, the desired tandem
cyclization product 32 was isolated along with the arrested
intermediate 33 in an overall 34% yield.17 Both products can
Supporting Information Available: Experimental pro-
cedures as well as H NMR spectral and characterizations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
(16) For a related diastereoselective example, see: Yamauchi, T.;
Sugiyama, J.; Higashiyama, K. Heterocycles 2002, 58, 431.
(17) Compounds 32 and 33 are not separable. Also found on occasions
was the central-cyclized product as part of the inseparable mixture.
OL047572Z
(18) For a recent review on radical processes leading to bridged
azabicycles, see: Sato, T.; Ikeda, M. Heterocycles 2003, 59, 429.
778
Org. Lett., Vol. 7, No. 5, 2005